The Endoplasmic Reticulum (ER) functions primarily to process newly synthesized secretory and transmembrane proteins. However, abnormal accumulation of unfolded proteins in this compartment causes a state of “ER stress”, which is a hallmark feature of secretory cells and many diseases, including diabetes, neurodegeneration and cancer (Hetz et al., Nature Reviews Drug Discover 2013; 12, 703-719). Adaptation to protein-folding stress is mediated by the activation of an integrated signal transduction pathway known as the ER stress response, or the unfolded protein response (UPR). This coordinated pathway signals through three distinct stress sensors located at the ER membrane: IRE-1α. ATF6, and PERK (Hetz et al., Nature Reviews Drug Discover 2013; 12, 703-719). The most conserved arm of the UPR involves IRE-1α. During ER stress, this kinase oligomerizes, autophosphorylates, and uses its endoribonuclease activity to excise a 26-nucleotide fragment from the unspliced XBP1 mRNA (Yoshida et al., Cell 2001; 107; 881-891). These events give rise to functional XBP1, a potent multitasking transcription factor that promotes the expression of ER chaperones and regulates distinct sets of target genes in a cell type-specific manner (Acosta-Alvear et al., Mol Cell 2007; 27, 53-66; Lee et al., Mol Cell Biol 2003; 23, 7448-7459; Yoshida et al., Cell 2001; 107; 881-891). Importantly, while XBP1 has been shown to control the maintenance of various immune cells under non-pathological conditions, a role for this transcription factor as a negative regulator of anti-tumor responses and normal immune function in cancer has never been reported.
Aggressive tumors have evolved strategies to thrive in adverse conditions such as hypoxia, nutrient starvation and high metabolic demand. Cancer cells constantly undergo ER stress, but they ensure survival by adjusting the ER protein folding capacity via the UPR (Hetz et al., Nature Reviews Drug Discover 2013; 12, 703-719). In malignant cells, XBP1 confers drug resistance by preventing drug-induced cell-cycle arrest and mitochondrial permeability and apoptosis (Gomez et al., FASEB J 2007; 21, 4013-4027). XBP1 drives the pathogenesis of multiple myeloma (Carrasco et al., Cancer Cell 2007; 11, 349-360; Lee et al., Proc Natl Acad Sci USA 2003; 100, 9446-9951) and of chronic lymphocytic leukemia (Sriburi et al., J Cell Biol 2004; 167, 35-41). Further, it was recently demonstrated that XBP1 fosters triple-negative breast cancer progression by promoting tumor cell survival and metastatic capacity under hypoxic conditions (Chen et al., Nature 2014; 508, 103-107). While XBP1 expression in cancer cells has been shown to directly support tumorigenesis, the role of this ER stress sensor in sculpting a tumor-permissive immune milieu has not been established.
In most solid cancers, nonmalignant cells such as leukocytes, vascular cells and fibroblasts, stimulate tumor development and progression (Bhowmick et al., Nature 2004; 432, 332-337; Whiteside. Oncogene 2008; 27, 5904-5912). Leukocyte recruitment to established cancers results in diverse pro-tumoral effects including the secretion of growth factors that enhance tumor cell proliferation and metastasis (Coussens et al., Cell 2000; 103, 481-490; Coussens and Werb, Nature 2002; 420, 860-867; Mantovani et al., Nature 2008; 454, 436-444); the induction of tumor vascularization via paracrine mechanisms (De Palma et al., Trends Immunol 2007; 28, 519-524); and the orchestration of immunosuppressive networks (Zou, Nat Rev Cancer 2005; 5, 263-274) that restrain the protective role of the scarce leukocyte subsets with inherent anti-tumor capacity. Ovarian tumors subvert the normal activity of infiltrating dendritic cells (DCs) to inhibit the function of otherwise protective anti-tumor T cells (Cubillos-Ruiz et al., J Clin Invest 2009; 119, 2231-2244; Curiel et al., Nat Med 2003; 9, 562-567; Huarte et al., Cancer Res 2008; 68, 7684-7691; Scarlett et al., Cancer Res 2009; 69, 7329-7337; Scarlett et al., J Exp Med 2012). Eliminating or “re-programming” tumor-associated DCs (tDCs) in vivo has been demonstrated to abrogate ovarian cancer progression (Cubillos-Ruiz et al., J Clin Invest 2009; 119, 2231-2244; Curiel et al., Nat Med 2003; 9, 562-567; Huarte et al., Cancer Res 2008; 68, 7684-7691; Nesbeth et al., Cancer Res 2009; 69, 6331-6338; Nesbeth et al., J Immunol 2010; 184, 5654-5662; Scarlett et al., Cancer Res 2009; 69, 7329-7337; Scarlett et al., J Exp Med 2012), but the precise molecular pathways that tumors exploit in DCs to co-opt their normal activity remain poorly understood, and therefore available therapeutics are limited.